Understanding how variation in noncoding elements impacts the risk to complex diseases is the first step in determining what contribution gene regulation has in the disease process. This project aims to evaluate the biological significance of intron 13 in the calpain-10 gene, a type 2 diabetes candidate gene on chromosome 2q37. Previous DNA sequence analysis of CAPN 10 indicates a distinct excess of polymorphism in intron 13. As it is observed in multiple ethnic populations, this "peak of polymorphism" could be the result of an old balanced polymorphism, which occurred before the divergence of the major ethnic groups. Under the scenario of the "thrifty genotype" hypothesis, this signal of selection could indicate variants in a functionally important element that at one time conferred a selective advantage. Detailed case-control analyses, using both single SNPs and haplotypes, will be performed to describe the impact of this region on type 2 diabetes risk in two samples, Mexican-Amercians and European-Americans. In a concurrent study, we propose to perform a phylogenetic analysis to compare human CAPN10 intron 13 to homologous sequences in 9 non-human primates. Comparisons of sequence data from closely related species could pinpoint putative regulatory elements, areas that exhibit higher than average sequence conservation. This combined strategy of using human population genetics, disease association analyses, and evolutionary approaches could prove to be effective to elucidate the functional impact of noncoding elements on the risk of complex disease.